Fluid stimulation methods and devices for treating fluid overload

ABSTRACT

Methods for treating fluid overload in a subject comprise shifting fluids directly and non-invasively from an interstitial compartment of the subject to skin of the subject through controlled local sweating. Methods of the invention allow for removal of excess fluid from the interstitial compartment of the subject and treat fluid overload in the subject. Sweat stimulation systems comprise a chamber and first and second relative humidity sensors. The chamber is sized to fit around a body part of a subject, comprises an inlet and an outlet, and is configured such that air flows through the chamber from the inlet to the outlet. The first relative humidity sensor is operably located inside the inlet, and the second relative humidity sensor is operably located proximate the outlet.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S.Provisional Application No. 63/045,446, filed Jun. 29, 2020, and to U.S.Provisional Application No. 62/957,446, filed Jan. 6, 2020, and to U.S.Provisional Application No. 62/948,988, filed Dec. 17, 2019, and to U.S.Provisional Application No. 62/943,285, filed Dec. 4, 2019, and to U.S.Provisional Application No. 62/938,971, filed Nov. 22, 2019, and to U.S.Provisional Application No. 62/876,381, filed Jul. 19, 2019, the contentof which are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The invention generally relates to systems and methods of stimulatingfluid transfer through the skin in a subject for treating edematousclinical conditions in the subject.

BACKGROUND

Some patients suffer from chronic pathological conditions in which thereis an imbalance of fluids in the body. Congestive heart failure, forexample, occurs when fluid builds up around the heart. Because of theexcess fluid, the heart is unable to pump sufficiently to maintain bloodflow to meet the body's needs. A person suffering from heart failure mayexperience shortness of breath, exhaustion, rapid heartbeat, and swollenlimbs. Heart failure is a common, potentially fatal condition and is aleading cause of hospitalization in people over the age of 65.

In heart failure, the heart works harder to eject blood, leading to abuildup of blood pressure. When elevated blood pressure prevents fluidsfrom draining from the interstitial compartments of the body, edema, orswelling caused by fluid accumulation in bodily tissues, may occur. Theadditional work of the heart due to edema weakens the heart, furtherreducing the ability of the heart to function properly. The fluidaccumulation may lead to additional health conditions, hospitalization,and death.

Patients suffering from such conditions are typically treated on a dailybasis by oral drugs such as diuretics and on a weekly basis in hospitalsby using IV diuretics treatment. Most of those patients developresistance to the Diuretic treatment, worsening renal function and otherside effects thereby greatly reducing the efficacy of this the primarytreatment option.

SUMMARY

The invention provides methods and systems that remove fluid from thebody through controlled skin fluid transfer. The invention providesnon-invasive methods and systems designed for treating chronic patientsat home, at the clinics and in hospital thus allowing the patient togreatly reduce hospital visits and his reliance solely on pharmaceuticaltreatments.

Fluid flow, such as sweat flow, is directly connected to theinterstitial compartment. Sweat fluid is interstitial fluid that fillsthe sweat gland when triggered to do so. If controlled, sweat and otherfluid can be removed from the patient at a flow rate of up to 2 litersper hour. In some instances, local heat can be applied together withhumidity and airflow conditions to increase rate of fluid removal orsweating.

In other instances, neural stimulation of the sweat glands can producesweating. For example, neural stimulation may result from the use ofelectrodes on a body part of the patient. The electrodes deliverelectrical pulses to the body part. In some embodiments, the electrodesmay be disposed in a wearable cuff that fits around a body part. In someembodiments, the electrodes may be disposed in a patch that is arrangedon a body part.

In some instances, creation of osmotic pressures favoring outflow offluids from the body, other than through sweat glands, can be applied.In other instances, nutritional diet, mental parameters, orpharmacological or chemical administration can stimulate sweatproduction or fluid loss.

The invention provides methods and systems that remove fluid from thebody through controlled skin fluid transfer, independently andregardless of pharmaceuticals, nutrition, and mental condition.Moreover, the invention provides methods for removing excessinterstitial fluid by increasing sweat flow through the skin of apatient. The invention provides for removal of interstitial fluid fromany part of the body, such as, but not limited to, the lower limbs, theupper limbs, abdomen, chest, or back. Other embodiments allow forremoval of interstitial fluid through saliva production, which removesfluid through the mouth of a patient.

A wearable chamber is placed around a body part of the patient. Tostimulate sweat production, the chamber generates heat at controlledtemperatures between about 32° C. and about 50° C., controlled relativehumidity equal to or less than about 85% (e.g., less than 80%, less than75%, less than 70%, less than 65%, less than 60%, less than 55%, lessthan 50%, less than 45%, less than 40%, less than 35%, less than 30%,less than 25%, less than 20%, less than 15%, less than 10%, or less than5%, including any value in between the recited values) and controlledflow rate of between about 0.2 cubic meters per minute and about 4 cubicmeters per minute that stimulates sweat production. The gap between thepatient body and the wearable chamber wall can be any distance, andmight have direct contact in some points. The chamber can be flexible orrigid. In some instances, the chamber is completely sealed to air andhumidity. In other instances, the chamber is made of membrane thatallows certain evaporation of humidity and air passage.

One or more sweat content sensors determine the mineral compositionwithin the sweat and determine what additional food supplements, if any,are needed to balance the patient status. For example, supplements mayinclude sodium chloride, potassium, calcium, and magnesium. A remoteportal or programmer allows the treatment and sweat parameters to besent to a physician who can monitor the treatment remotely. The systemincludes one or more relative humidity sensors and one or moretemperatures sensors at the inlet, or inlet pipe, of the apparatus andone or more sensors close to the outflow of the air in the apparatus.The system also includes one or more flow meters at the inlet on whichthe body part is within. The sweat rate and its accumulated amount perhour is calculated by the device as a function of the flow rate in thedevice multiplied by the changes of absolute humidity between the inletand outlet of air flow. The absolute humidity is automaticallycalculated by knowing the relative humidity and temperature. The sweatrate is presented to the user and can be sent remotely to a treatingphysician.

In some embodiments, the device measures fluid loss during the treatmentby measuring the patient body weight before, during, and after thetreatment. One or more temperature sensors or sweat sensors might beplaced on the patient body inside of the chamber, such as on a face or aneck of the patient, in order to provide a reference measure of sweatand skin temperature during treatment.

In certain aspects, the invention is directed to methods for treatingfluid overload in a subject. The methods comprise shifting fluidsdirectly and non-invasively from an interstitial compartment of thesubject to skin of the subject through controlled local sweating,thereby removing excess fluid from the interstitial compartment of thesubject and treating fluid overload in the subject. Sweating isstimulated by controlling relative humidity and temperature within achamber.

Methods of the invention further comprise calculating a sweat ratewithin the chamber. The methods further comprise analyzing sweat contentand recommending nutritional supplement. In some embodiments, themethods comprise aerobic or anaerobic exercising of a body part of thesubject within the chamber to encourage sweating without increasing thecore temperature of the body by more than 0.5° C. In some embodiments,the method further comprises controlling and monitoring conditions ofthe chamber using a controller, wherein the controller is operable by auser to program conditions of the chamber. In some embodiments of theinvention, the method is carried out using a sweat stimulation system.

In certain aspects, the invention is directed to a sweat stimulationsystem. The sweat stimulation system comprises a chamber and first andsecond relative humidity sensors. The chamber is sized to fit around abody part of a subject, leaving clear volume of air between the bodypart and walls of the chamber, comprises an inlet and an outlet, and isconfigured such that air flows through the chamber from the inlet to theoutlet. The first relative humidity sensor is operably located proximatethe inlet, within the inlet pipe that drives the air from the heatgenerator to the chamber so that it can pick up all the air that flowsinto the chamber, and the second relative humidity sensor is operablylocated proximate the outlet. The heat source can be part of the chamberwall or can be placed next to the chamber wall, and the heat will betransferred to the chamber by a certain line or tubing. Similarly, theair fan can be part of the chamber wall or may be placed next to thechamber wall and transfer the air to the chamber by a certain line ortubing.

In certain embodiments, the system has a skin temperature sensor that isplaced on the skin of the patient. The skin temperature sensor monitorsthe skin temperature and verifies that the skin temperature does not, inany circumstance, elevate above 39° C. If the skin temperature elevatesabove 39° C., the system stops operation of the device or reduces itsinflow temperature or airflow rate. In some embodiments, the skintemperature sensor sends values to a controller, wherein the controllercalculates sweat rates from humidity sensors and ensures that air flowin temperature is optimized relative to the skin temperature sensor. Forexample if the skin T reads 34° C. and the sweat rate is only 100 ml/hrthen the controller will elevate the ambient air temperature till thesweat rate is 300 ml/hr or that the skin T has elevated over 38° C.(whichever comes first).

The system further comprises a controller communicatively coupled with aplurality of sensors that provide data to the controller for calculatingsweat rate within the chamber, the controller comprising a processorconfigured to control and monitor conditions of the chamber and operableby a user to program conditions of the chamber. In certain embodiments,the system comprises a body scale to measure the body weight of thepatient. In some embodiments, the system comprises a clock to measurethe duration of the treatment.

The system further comprises an air fan coupled to the chamber. In someembodiments, the system further comprises inflow and outflow flow metersassociated with the air fan. The flow meters are communicatively coupledwith the controller and data from the flow meters is used forcalculation of the sweat rate within the chamber. The controller is usedto analyze sweat content and recommend nutritional supplement.

The system further comprises an exercise device disposed in the chamber,the exercise device for use by the patient to encourage sweating. Theexercise device comprises a pedal exercise device or a spring exercisedevice for anaerobic exercise that will not elevate the core temperatureof the body by more than 0.5° C. The body part comprises one or morelegs, one or more arms, a torso, lower back, and abdomen up to the levelof the chest and below the level of the heart. An interior of thechamber is configured such that walls of the chamber are kept spacedfrom the body part of the subject.

In some embodiments, the system comprises a blood pressure monitor,heart beat monitor, and core body gauge to monitor the patientparameters during the treatment. The system stimulates fluid losswithout changing the patient blood pressure, core temperature, orheartbeat. In certain embodiments of the invention, the chamber is fixedto a surface, such as a bed or chair. In other embodiments, the chamberis mobile or wearable by a patient.

In such a system, an apparatus such as a cuff or chamber that creates acontrolled temperature, pressure, and humidity environment can be placedon a patient's arm, leg, abdomen, back, or a combination thereof. Thechamber can be worn at home for about a few hours. Wearing the chamberfor the short duration will result in sweat formation from the heatgenerated.

The sweat can be monitored, and its content collected and evaluated toassess the edema status and to determine if the patient needs to takesupplements, such as minerals or other additives, to preserve correctblood count. The chamber can generate results of the fluid removal,including sweat content status and heat generation, for display on auser interface or for transmitting to network for monitoring by aphysician that is remote. The patient can apply the treatment forduration throughout the day, at home, and use the treatment to balancefluid status.

In certain embodiments, devices of the invention further comprise asystem that records treatment parameters and results. The system isconfigured to transfer the data by wireless or any other communicationmethod to a medical center for analysis and control.

In some aspects, the invention provides a fluid removal treatment devicethat a patient can use on the go or from the comfort of their own home.In particular, some embodiments of the invention provide a portabledevice that can be worn for a few hours or may be worn overnight toremove excess interstitial fluid by inducing sweat. The device comprisesan apparatus such as a cuff, chamber, or sleeve that creates acontrolled environment around the patient's body part, such as, an arm,leg, abdomen, back, or a combination thereof. In certain instances, thedevice can be used to reduce afterload by heating and increasingcutaneous vascular conductance. As such, using the device overnight isuseful for treating dyspnea and/or orthopnea to improve sleep. In someembodiments, the invention provides a mobile apparatus such as a cuff,chamber, or sleeve that a patient can wear around a body part tostimulate fluid loss while the patient is moving around. The apparatusmay be designed to allow freedom of movement so that the patient wearingthe apparatus can, for example, cycle or jog in it. The apparatus may beworn to improve exercise tolerance and health status of patients byreducing breathlessness. In some instances, the apparatus is sized forwearing underneath the patient's clothes so that it is less apparent.

In some embodiments, the chamber is a rigid or flexible cuff that fitsaround one or two legs, one or two forearms, an abdomen, or a back of apatient. One side of the cuff has an entrance to relatively dry airsupply. The air humidity is monitored at the inflow, and air attemperatures ranging from about 32° C. to about 50° C. at a relative lowhumidity of less than about 85% are fanned into the cuff. The relativelow humidity may, for example, be about 85%, 80%, 75%, 70%, 65%, 60%,55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. The outlet forthe air is at a torso or a lower back of the patient, and the air outletis monitored by a relative humidity sensor. The sweat amount can becalculated and displayed on a user interface. The sweat amount, or sweatrate, calculated is the difference between the absolute humidities atthe inflow and the outflow multiplied by the airflow rate.

In some embodiments, the chamber is sized to fit around a patient'sabdomen, one or two legs, one or two arms, a back, or any combinationthereof. In some instances, the chamber may cover a substantial portionof the patient's body below the chest, for example, covering around 1square meter of surface area and providing fluid loss at a rate ofapproximately 200 ml/hr. The patient can request, or be prescribed, acertain amount of fluid skin transfer per treatment. The systems of theinvention will calculate sweat rate, display, and stop the operation ofthe system once the desired sweat amount is obtained. Calculation can beperformed using input from the two humidity sensors and their differencein readings over time, such as every few minutes.

In other instances, creation of an osmotic pressures favoring outflow offluids from the body, not through sweat glands, can be applied. Forexample, in some embodiments, the fluid can be stimulated by a chamberthat has a wet environment with specific and controlled mineral content,primarily salts and electrolytes such as sodium potassium and chloride.The mineral content drives fluids out of the body by the mechanism ofosmosis and also balances the electrolytes and mineral composition ofthe fluids as required in the body.

In some embodiments, the invention is directed to a method of removingfluids through the skin by osmosis. The method comprises fitting achamber around a body part of a patient, the chamber comprisinginterstitial electrolytes. The method further comprises controllingcontent and concentration of the interstitial electrolytes in thechamber, thereby driving water and salts out of the body part of thepatient while maintaining pH and electrolyte levels of the body part.

In some embodiments of the invention, fluid loss may comprise salivageneration. The saliva glands can produce up to about 2.5 liters offluid per day. Stimulation of saliva glands can be achieved by chewinggum or any other material suitable as a stimulator. The saliva can becollected, measured, and analyzed. The system might have a flavor, suchas a flavored mouthpiece, that will stimulate production of saliva.

In certain embodiments, the invention is directed to a fluid lossstimulation device comprising a housing. The housing comprises amouthpiece, a storage chamber, and suction. The mouthpiece is disposedat a proximal end of the housing. The device comprises a power buttonfor providing power to the suction. For example, battery power may beused to power the suction, which may be any suitable suction component,such as a pump. The suction is configured to deposit saliva from a mouthof a patient into the storage chamber of the device. The storage chamberis removably detachable from the device. For example, the storagechamber may comprise a threaded end that is couples with threads on abody of the device. Rotation of the storage chamber results indetachment of the threaded components.

Another aspect of the invention is based on the recognition that it maybe important to maintain a balanced level of sodium in the body whilefluid is removed from the body during the sweating process or also whentrying to maintain electrolyte balance of a patient suffering fromimbalances of the electrolytes in the body especially potassium, sodium,chloride and carbonate. Sweat is isotonic in the sweat gland. As sweatmoves through the skin and out of the body, a portion of sodium from thesweat is re-absorbed back into the body to maintain a proper saltbalance in the body. However, in certain instances, the induction ofsweating can lead to salt imbalance since water is driven out of thebody while sodium is re-absorbed. Methods and systems of the inventionthus include the insight to prevent this imbalance by introducingnegative ions into the airflow. When negative ions are introduced intothe airflow, sodium, which is positively charged, is driven towards theskin surface by the ion bond strength and as a result re-absorptiondecreases, thereby preventing a salt imbalance.

In certain aspects, methods and systems of the invention provide a fluidstimulation system with a chamber sized to fit around a body part of asubject to stimulate fluid loss. The chamber is sized to leave a clearvolume of air between the body part and walls of the chamber. Thechamber further includes an inlet and an outlet and is configured suchthat an air flow passes through the chamber from the inlet to the outletwhilst circulating evenly throughout the body surface. The air flowincludes negative ions introduced by a component of the system. Forexample, one of carbonate, sulphate, bromide, chloride, fluoride,iodide, nitride, oxide, or sulfide ions may be introduced into theairflow by the component of the system. In certain instances, thecomponent is an ion resin located near the inlet of the chamber.Alternatively, the component is a negative ion generator that is locatedat the inlet of the chamber. Introducing negative ions into the fluidstimulation system is useful for inhibiting sodium re-absorption duringfluid loss, thereby preventing a salt imbalance. Such methods mayinvolve introducing negative ions (e.g., one of carbonate, sulphate,bromide, chloride, fluoride, iodide, nitride, oxide, or sulfide ions)into the airflow to inhibit sodium re-absorption during sweating.

In other instances when the electrolyte balance is such that the patienthas hyponatremia, positive ions (cations) will be dissolved into thehumid air flow (relative humidity between 40%-85% to enable maximalamount of cations to be dissolved in the water molecules in the air).This way when the patient sweats the sodium will repel the sodiumflowing to the surface and increase the sodium concentration in theinterstitial compartment and then in the plasma.

In other aspects, this disclosure provides methods and devices to reduceedema by enhancing fluid transfer through the skin while maintainingpatient mobility.

For example, in some embodiments this disclosure provides a mobilesystem. The mobile system comprises a wearable capsule and a console, toelevate skin temperature so as to initiate sweat production. Forexample, a wearable device may be provided to create a warm airenvironment at a predetermined volume around the body to initiate sweatproduction and reduce symptoms of edema. Methods and devices may becontrolled by smartphone application.

In some aspects, this disclosure provides a method to reduce Orthopneaand Paroxysmal Dyspnea (PND) shortness of breath and enable supineposition sleeping and/or enhanced diuresis when laying down. The methodpreferably reduces blood pressure and enables diaphragm full inspirationstretching.

In some instances, this disclosure may provide an apparatus thatincreases a temperature at a part of portion of a subject's body tocreate vasodilation of the vasculature, thereby reducing pressures andalleviating symptoms such as a shortness of breath. Devices of theinvention may provide an apparatus that pushes the abdomen away from thediaphragm by actively pressing or pulling the abdomen towards thepelvis.

In yet another aspect, this disclosure may provide a method to reducesodium concentrations in the plasma and interstitial compartment byenhancing sweat rate and drawing to a surface of skin sodium cations.The sweat may be drawn to the surface of the skin with air comprised ofnegatively charged anions.

In other aspects, disclosure provides an apparatus for enhancing sweatwith warm air that is delivered into a wearable apparatus around asubject's body. Delivering the warm air into the wearable apparatus mayresult in elevated skin temperatures to levels of between about 33-39degrees Celsius. In some instances, the invention provides for a warmhumid air inline pipe comprising two-stage disposable apparatus. A firststage may comprise a disperser that dispenses a soluble salt into thehumid air. Preferably, as the air flows through the disperser, the airbecomes full with ions. A second stage may be configured to pass the ionfilled air through a cation resin filter. The warm air that exits thefilter and flows around the skin will be negatively charged at huminitesof, for example, around 50. This air when flowing around the sweatingskin will pull the sodium ions to the skin surface and reduce itsreabsorption

In yet other aspects, this disclosure provides a method for removingfluid overload from the interstitial and intravascular compartments bypromoting fluid flow from eccrine sweat glands and out of the skin byelevating body skin temperature. Alternatively, or in addition to, thisdisclosure provides a method for controlling skin temperature and sweatrate by closing a control loop inputting relative humidity at the inflowand the outflow, the air flow rate and the skin temperature and changingthe flow rate and inflow air temperature until a sufficient sweat rateis achieved. The apparatus may have a weight built in that inputs thebaseline and final weights to the system that can then send theinformation, for example, by the internet, to the treating physician.The apparatus may be worn around a body part, for example, from thechest and upper back down to the feet and toes. The apparatus may enablefree flow of air inside the apparatus and evaporate all the sweat as itincreases the air flow rate to ensure that the relative humidity is lessthan 70%. The apparatus may have a cross section with a mesh fabric thatcontacts the skin at very small area thus enabling free flow and sweatevaporation in maximal areas. The apparatus may have an airflowdispersion system incorporated inside the mesh that spreads the airevenly in the wearable thus ensuring homogenous temperatures around thebody and by such optimizing total sweat rate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of the relationship between water gain and waterloss in the body.

FIG. 2 is a diagram of the relationship of fluid compartments of thebody.

FIG. 3 is a diagram of filtration in systemic capillaries.

FIG. 4 is an image of a medical condition with excess fluid in thechest.

FIG. 5 is an image of a medical condition with excess fluid in the legs.

FIG. 6 shows sweat flow from A) arm, B) thigh, C) abdomen, and D) lowerback) when subjected to local heat elevation.

FIG. 7 shows effects of internal and average skin temperatures on localsweating rate.

FIG. 8 shows plots of sweat rate for two subjects.

FIG. 9 is a plot of sweat rate increase to basal rate of sweatproduction.

FIG. 10 shows sweat rate as a change in core temperature from pre-heatstress.

FIG. 11 shows an embodiment of a system of the invention.

FIG. 12 shows an embodiment of a system of the invention.

FIG. 13 shows an embodiment of a system of the invention.

FIG. 14 shows an embodiment of a system of the invention.

FIG. 15 shows an embodiment of a system of the invention.

FIG. 16 shows an embodiment of a system of the invention.

FIG. 17 shows an embodiment of a system of the invention.

FIG. 18 shows an example configuration of a device of the invention.

FIG. 19 shows an exemplary apparatus of the invention.

FIG. 20 shows a side view of a wearable apparatus of the invention.

FIG. 21 shows a front view of a wearable apparatus of the invention.

FIGS. 22 & 23 show a cross sectional view of a wearable apparatus of theinvention.

FIG. 24 shows another view of a wearable apparatus of the invention.

FIG. 25 shows a diagram of a system algorithm of the invention.

FIG. 26 shows results from 4 hours experiment on HF, fluid overloadedpatients.

FIG. 27 shows an exemplary calculation performed from the onlinehumidity sensors and the air flow meter.

FIG. 28 shows results a patient treatment.

FIG. 29 shows a built-in algorithm executable by a counsel of theinvention.

FIG. 30 shows clinical data from six treated subjects.

FIG. 31 shows treatment results from using systems and methods of theinvention.

FIG. 32 shows clinical data from using systems and methods of theinvention.

FIG. 33 shows clinical data from using systems and methods of theinvention.

FIG. 34 shows clinical data from using systems and methods of theinvention.

DETAILED DESCRIPTION

The invention provides methods and systems for removing excess fluid ina patient by using externally stimulated and increased sweat rates.Systems of the invention include a home-use, an outpatient clinic or inhospital device for chronic patients that need to decongest fluidoverload. The device is easily adjustable between treatment areas, iseasy to operate and monitor, and is easy to clean and maintain.Embodiments of the device are portable, although the device can bestatic during treatment episodes.

The invention also allows for reading and monitoring of fluid removed,as well as the contents of the fluid. Treatment episodes can be localand isolated to body parts such as the leg, arm, abdomen, and back andcan also be applied to combination of the body parts such as the legs,torso, back and abdomen. Sweating can be regulated during treatment toallow for fluid flow from the skin of 500-2000 milliliters per day. Theinvention allows patients to ensure no skin or other heat injuries occurduring the treatment and there are no unacceptable losses orconcentration gain of electrolytes or salts that cannot be reabsorbed ordigested back. Moreover, sweating is a process that most patientstypically have experienced, and adverse effects to the skin areunlikely, even in severe heart failure patients.

Fluid transfer from the interstitial and intravascular compartment canbe stimulated and enhanced via sweat, osmosis, other fluid transfer, ora combination thereof using local elevation of skin temperatures orincrease in ambient osmotic pressure favoring fluid transfer from theinterstitial compartment to outside the body.

In some embodiments, neural stimulation of the sweat glands can producesweating. For example, neural stimulation may result from the use ofelectrodes on a body part of the patient. The electrodes deliverelectrical pulses to the body part. In some embodiments, the electrodesmay be disposed in a wearable cuff that fits around a body part. In someembodiments, the electrodes may be disposed in a patch that is arrangedon a body part. The electrodes may provide stimulation of nerves, suchas peripheral nerves. Any suitable electrodes may be used, such aselectrodes produced by MicroProbes for Life Science (Gaithersburg, Md.,USA).

In some embodiments, creation of osmotic pressures favoring outflow offluids from the body, other than through sweat glands, can be applied.In other embodiments, nutritional diet, mental parameters, orpharmacological or chemical administration can stimulate sweatproduction. Examples of pharmacological or chemical products includezinc supplements and neuropsychiatric drug desipramine, such asNORPRAMIN (manufactured by Sanofi-Aventis U.S. LLC, Bridgewater, N.J.,USA) may induce sweating.

Sweat rates, when the skin is exposed to local, tolerable temperatureelevations of about 1° C. to about 10° C. elevating it to levels between32° C. to 40° C., can be in the rate of about 0.5 milligram per cm² perminute. Such a rate translates to a sweat rate of over about 200milliliters/hour from body parts having a surface area of around 10,000cm² which is the average body surface area of both legs torso. The sweatrate is calculated using the following formula.

sweat rate=(absolute humidity out−absolute humidity in)×airflow

The invention may be used for patients of different ages. As reported ina study from Miranda A. Farage et al., Textbook of Aging Skin,thermoregulation effects were evaluated for a group of younger subjects(21-39 years in age) and a group of older subjects (61-73 years in age).Sweat responses, esophageal, skin temperatures, non-evaporative heatexchange, heart rate, cardiac output, blood pressure, forearm bloodflow, and metabolic heat production were examined after exposing thesubjects to 40° C. and 40% relative humidity for up to 130 minutes. Thestudy reported that there was no significant difference in sweat rate oronset of sweating between the groups. Therefore, with age, sweat ratesand changes with sweat rates can still be high enough to promotedecongestion treatment in patients chronically overloaded with fluid.

Sweat rate is typically not affected by medical conditions such ascongestive heart failure (CHF). Furthermore, sweat rate is not reducedin CHF patients. Sweat rate may even be higher in CHF patients becauseSSNA activity is not altered compared to a control. Whole body heatinginduces significant sweating responses, while the sweat rate toward theend of a moderate whole body heating in CHF patients is marginally lower(˜20%) than that of control subjects. In CHF patients, SSNA and sweatrate increased during the initial period of whole body heating (e.g.,internal temperature increase ˜0.2-0.3° C.), while neither increased inhealthy controls during this period.

However, cutaneous vascular conductance is reduced in heart failurepatients, and skin can be more vulnerable to heat injury if exposed toheat exposure that is too high or too long in duration. CHF compensatorymechanisms typically do not allow too much peripheral vasodilation in anattempt to preserve cardiac output to vital organs. In some aspects ofthe invention, a skin temperature sensor determines the inflow airtemperature and rate thus the ambient air temperature surrounding theskin. In cases where the CVC is markedly reduced it will not effectneither sweat rates nor the safety of the procedure as the required skintemperature will be achieved at a lower inflow air temperature and theonset of sweating will be at a lower ambient temperature. The skintemperature will always be maintained below 39° C. and so sweat ratesand safety will be preserved even if CVC is reduced. Cutaneousvasodilation evoked by heat exposure may decrease afterload, and in turnimprove vasodilatory response to stress. In CHF patients, reductions incardiac output lead to an increase in vascular resistance, which mayadversely affect the ability of the peripheral vascular to dilate inresponse to heat and exercise stress. Warm temperatures may beneficiallyaffect peripheral resistance and cardiac output in CHF subjects and maybe responsible for lower death rates during summer months. Studies havesuggested that thermal therapy, such as a warm water bath, sauna, or drysauna, can be considered in CHF subjects to increase cardiac output andejection fraction, and improve left ventricular function, endothelialfunction, and the quality of life in CHF patients.

The content of sweat is derived from the content of interstitial fluid,which is mostly water. Sweat is hypotonic, with electrolytes and salts,some of which are reabsorbed. Throughout therapy, the sweat content canbe monitored to ensure that there is not too much loss of electrolytesand salts in the patient.

In the invention, local heat provides an environment that allows forsweating of the body part where sweat evaporates quickly from the skinand the environment keeps the skin moist and well-nourished during theprocedure. Sweat can be stimulated to result in a local limb fluidremoval rate of over about 100 milliliters/hour. Treatments for thelocal body part can be short in duration and administered throughout theday, resulting in treatment of about a few hours overall in a day.

Water is an important part of the body and of bodily functions. In thebody, fluid typically does not accumulate because water gain istypically equal to water loss. As shown in FIG. 1 , for a 2500 mL volumeof water, water gain occurs through metabolic water (200 mL), ingestedfoods (700 mL), and ingested liquids (1600 mL), while water loss occursthrough the GI tract (100 mL), lungs (300 mL), skin (600 mL), andkidneys (1500 mL).

Total body water volume is typically 40 L and accounts for 60% of bodyweight. Normal fluid compartments in the body include extracellularfluid (ECF) volume (15 L, 20% of body weight) and intracellular fluidvolume (25 L, 40% of body weight). The ECF includes plasma volume (3 L,20% of ECF) and interstitial fluid volume (12 L, 80% of ECF). FIG. 2shows a diagram of the relationship of fluid compartments of the body.

In the body, fluid transfer happens across capillaries. Fluid isfiltered from the arterial side of capillaries to the interstitialcompartment at a rate of about 22 L/day. FIG. 3 shows a diagram offiltration in systemic capillaries.

In some medical conditions, such as those shown in FIG. 4 and FIG. 5 ,patients suffer from elevated capillary hydrostatic pressure, whichleads to accumulation of fluids in the interstitial compartment. Bloodflow to the skin may also be reduced.

Conventional therapies for prevention of fluid overload are directed toreducing intravascular pressure by reducing blood volume. Diuretic pillsincrease urine output, which leads to reduced intravascular volume andpressure. With time, patients respond less well to diuretic therapy andrenal function is reduced. Patient prognosis is poor, with close to 50%not surviving more than five years after first diagnosis.

Methods of the invention can be administered alone or in combinationwith diuretics to improve the outcome. The invention provides systemsand methods for treating fluid overload in a patient by removing excessfluid with controlled skin fluid transfer.

Sweating is one way the body releases fluids. Sweat pathways includeeccrine glands or major sweat glands located throughout the entire body.Eccrine glands can secrete up to 2 L/hour of fluids directly from theinterstitial compartment, and total body fluid loss from sweat can bemore than 10 L/day. Sweat is 98-99% water with some electrolytes, suchas sodium and chloride. Sweat also contains sodium chloride (NaCl),fatty acids, lactic acid, citric acid, ascorbic acid, and urea. Sweat ishypotonic at the skin surface and is a clear, odorless acid having pHthat ranges from about 4 to about 6.8.

The hypothalamus regulates sweat and homeostasis. The hypothalamussenses a rise in temperature and sends signals via the nervous system.Sweat glands receive the signals and secrete sweat. Blood vesselsreceive the signals and dilate. The sweat secretion and blood vesseldilation lead to homeostasis where the internal body temperature isabout 36° C. to about 38° C. In the body, the antidiuretic hormone (ADH)enhances fluid retention by making the kidneys reclaim more water. Therelease of ADH is triggered when osmo-receptor cells in the hypothalamusdetect and increase in the osmolarity of the blood. Homeostasis isachieved by encouraging thirst, as drinking reduces blood osmolarity toa set point, and increased permeability, as water reabsorption helpsprevent a further osmolarity increase. Furthermore, therenin-angiotensin-aldosterone system (RAAS) leads to an increase inblood volume and pressure to achieve homeostasis. The juxtaglomerularapparatus (JGA) responds to low blood volume or blood pressure, such asfrom dehydration or loss of blood. The JGA produces renin which leads toangiotensinogen and angiotensin II, which leads to arterioleconstriction. Angiotensin II is also detected by the adrenal gland,which in turn produces aldosterone, leading to increased sodium andwater reabsorption in distal tubules.

Providing a controlled environment can lead a patient to produce sweat.One way to increase sweat production is to elevate the local skintemperature for the patient. FIG. 6 shows sweat flow from specificorgans (A: arm, B: thigh, C: abdomen, and D: lower back) subjected tolocal heat elevation. FIG. 7 shows a plot of the effect of T_(es)(internal temperature) and

_(s) (average skin temperature) on local sweating rate with local (undersweat collection capsule) skin temperature equal to 34.8° C. FIG. 8shows plots of sweat rate for Subject 1 and Subject 2 that increaseagainst the basal level of sweating for the two subjects, as reported ina study with an increase in sweat rate with 5° C. rise in skintemperature by local irradiation. Solid circles denote thermal sweatingand open circles denote drug-induced sweating. FIG. 9 is a plot showingthat sweat rate increase is proportional to basal rate of sweatproduction, as reported in a study with an increase in sweat rate with5° C. rise in skin temperature by local irradiation. FIG. 10 shows sweatrate as a change in core temperature from pre-heat stress. As the changein core temperature from pre-heat stress increases, the sweat rateincreases.

Methods of the invention allow fluids to shift directly andnon-invasively from the extracellular compartment to the skin bycontrolled local sweating or in conjunction with osmotic regulation.Additional fluid output from sweat a few times per day is beneficial inavoiding edema formation. For example, fluid output may be in the rangeof about 100 milliliters/hour to about 300 milliliters/hour.Vasodilation of the skin area under high temperatures will increaseblood flow to the skin and the result of vasodilation will also assistin pathologies requiring enhanced blood flow.

The invention provides ergonomic, easy to use sweat stimulators. In someinstances, the sweat stimulators are designed to fit around limbs, suchas one or more arms or legs, a torso, abdomen, or lower back. Regulationof the local skin heat, oncotic pressure gradients, and evaporationrates of targeted organs accelerates fluid transfer through skin andreduces local edema. Moreover, the sweat content can be monitored andsupplements can be given, if needed.

In certain aspects, the invention is directed to fluid stimulationsystems or sweat stimulation systems comprising a chamber and first andsecond relative humidity sensors. The chamber is sized to fit around abody part of a subject, leaving clear volume of air between the bodypart and walls of the chamber, comprises an inlet and an outlet, and isconfigured such that air flows through the chamber from the inlet to theoutlet. The first relative humidity sensor is operably located insidethe inlet air pipe leading the air into the chamber. The inlet pipedrives the air from the heat generator to the chamber so that it canpick up all the air that flows into the chamber. The second relativehumidity sensor is operably located proximate the outlet.

The system further comprises a controller communicatively coupled with aplurality of sensors that provide data to the controller for calculatingsweat rate within the chamber, the controller comprising a processorconfigured to control and monitor conditions of the chamber and operableby a user to program conditions of the chamber. The controller is alsoused to analyze sweat content and recommend nutritional supplement.

A heat source can be part of the chamber wall or can be placed next tothe chamber wall, and the heat will be transferred to the chamber by acertain line or tubing. Similarly, the air fan can be part of thechamber wall or may be placed next to the chamber wall and transfer theair to the chamber by a certain line or tubing.

The system further comprises a gas mixture with or without air. Thesystem further comprises an air fan and heat source coupled to thechamber. The system further comprises an inflow flow meter associatedwith the air fan. The flow meter is communicatively coupled with thecontroller and data from the flow meters is used for calculation of thesweat rate within the chamber.

In certain embodiments, devices of the invention further comprise asystem that records treatment parameters and results. The system isconfigured to transfer the data by wireless or any other communicationmethod to a medical center for analysis and control.

In some embodiments, the system comprises a blood pressure monitor,heart beat monitor, and core body gauge to monitor the patientparameters during the treatment. The system stimulates fluid losswithout changing the patient blood pressure, core temperature, orheartbeat. In certain embodiments of the invention, the chamber is fixedto a surface, such as a bed or chair. In other embodiments, the chamberis mobile or wearable by a patient.

In certain embodiments, the system comprises a body scale to measure thebody weight of the patient. In some embodiments, the device measuresfluid loss during the treatment by measuring the patient body weightbefore, during, and after the treatment. One or more temperature sensorsor sweat sensors might be placed on the patient body outside of thechamber, such as on a face or a neck of the patient, in order to providea reference measure of sweat and skin temperature during treatment. Insome embodiments, the system comprises a clock to measure the durationof the treatment. In some embodiments, the system further comprises askin temperature sensor. The skin temperature sensor is placed on theskin of the patient and monitors the skin temperature and verifies thatthe skin temperature does not, in any circumstance, elevate above 38° C.If the skin temperature elevates above 38° C., the system stopsoperation of the device.

The system further comprises an anaerobic exercise device disposed inthe chamber, the anaerobic exercise device for use by the patient toencourage sweating. The exercise device comprises a pedal exercisedevice or a spring exercise device for anaerobic exercise that will notelevate the core temperature of the body by more than 0.5° C. The bodypart comprises one or more legs, one or more arms, a torso, a lowerback, or an abdomen. The abdomen comprises up to a chest level and belowa heart level. An interior of the chamber is configured such that wallsof the chamber are kept spaced from the body part of the subject. Insome embodiments, walls of the chamber have direct contact with the bodypart.

In certain aspects, the invention is directed to methods for treatingfluid overload in a subject. The methods comprise shifting fluidsdirectly and non-invasively from an interstitial compartment of thesubject to skin of the subject through controlled local fluid loss,thereby removing excess fluid from the interstitial compartment of thesubject and treating fluid overload in the subject. In some cases, thefluid loss is sweating. The fluid loss, or sweating, is stimulated bycontrolling humidity, airflow, pressure, and temperature within achamber. The methods further comprise calculating a sweat rate withinthe chamber. The methods further comprise analyzing sweat content andrecommending nutritional supplement. In some embodiments, the methodsfurther comprise aerobic or anaerobic exercising of a body part of thesubject within the chamber to encourage sweating without increasing thecore temperature of the body by more than 0.5° C.

In some embodiments of the invention, the method is carried out using afluid stimulation system or sweat stimulation system. The fluidstimulation system, or sweat stimulation system, comprises a chamber andfirst and second relative humidity sensors coupled with temperaturesensors. The chamber is sized to fit around a body part of a subject,leaving clear volume of air between the body part and walls of thechamber, comprises an inlet and an outlet, and is configured such thatair flows through the chamber from the inlet to the outlet. The firstrelative humidity sensor is operably located inside the air inlettubing, and the second relative humidity sensor is operably locatedproximate the outlet holes. A plurality of sensors provides data to acontroller for calculating sweat rate within the chamber. The methodfurther comprises controlling and monitoring conditions of the chamberusing the controller, wherein the controller is operable by a user toprogram conditions of the chamber. The method further comprisesmonitoring skin temperature of the subject and stopping operation of thesystem if the skin temperature exceeds 38° C.

FIG. 11 shows an embodiment of a system of the invention. A patient hashis legs inserted in a chamber. The patient's legs are fully inserted inthe chamber and the chamber end distal from the heat generator and fanis at a lower back or lower chest (torso) level of the patient. A heatgenerator and fan generate airflow between about 0.1 to about 4 cubicmeters per minute. The airflow path travels from the heat generator andfan into one end of the chamber through an inlet at the patient's feet.An inflow meter is disposed at the inlet.

Inside the chamber is a device or mechanism that encourages anaerobicfoot exercise (FIG. 13 ), such as a paddle or passive spring, in orderto enhance sweating. Foot exercise performed may be anaerobic andaerobic within the device in order to further enhance sweat rate

The chamber is sealed, with at least one inflow and at least one outflowand a combination of humidity sensors at the inflow and outflow toenable calculation of the sweat rate. Airflow travels through thechamber and out and outlet of the chamber. Controllers arecommunicatively coupled with sensors and measure conditions of thechamber. For example, relative humidity and temperature in are measuredat the inlet, and relative humidity and temperature out are measured atthe outlet. The system also includes a controller that provides feedbackof sweat rate and weight loss.

The invention allows for the skin to stay dry throughout the treatment.This is important because sweat that does not evaporate will slow downany further sweating and will also create an uncomfortable feeling forthe patient. Anywhere there is contact between the patient and thechamber, the airflow is reduced and sweat can accumulate, resulting inless efficient sweating. Accumulation of sweat is prevented by keepingthe body slightly away from the interior of the chamber. Using adisposable “net” within the chamber or having the patient wear thickclothing are two examples of how to keep the body slightly away from theinterior of the chamber, thereby keeping body parts away from directcontact with the chamber. Disposable cloth may also be used to keep thebody slightly away from the interior of the chamber, and would provide abenefit during cleaning of the chamber between treatments.

FIG. 12 shows an embodiment of a system of the invention. The basemattress is foldable and can be placed on a chair, couch, or a bed. Thehalf circular closing part is based on two foldable quarter circulartent-like structures that, when brought together over the patient's legsand torso, can then be hooked together or zipped to create a sealedchamber insulated against rapid heat loss from its outer surface. Thehot air, at a temperature of about 35° C. to about 50° C., enters fromtubes at either side of the mattress, is directed inwards, and hasvarious enlarging locations so that the warm air will flow up from itsbottom input location. This type of air outflow from bottom to top, withlarger holes towards the outflow, provides for uniform temperature ofthe air inside the chamber. Uniform temperature distribution inside thechamber is important because an optimal temperature for sweating isbetween about 36° C. and about 39° C. Therefore, keeping the airflow inall parts of the body uniform allows for optimal sweat rates andavoidance of heat damage to the skin. The hot air leaves the sealedchamber at holes created in the flexible fabric part, such as neoprene,around the torso. Typically the patient will decide if to be in bed orcouch and then set up the mattress. Next the patient connects the heaterto the inlet hose and gets situated on the mattress. The patient bringsboth quarter circular parts around the body of the patient and zips fromthe legs up all the way up to the level of the abdomen around the levelof the lower ribs to create a chamber.

FIG. 13 shows a foot exercise device. An anaerobic spring exercisedevice is shown in the chamber for use by the patient. The patient useshis or her feet to operate the anaerobic spring exercise device, therebyencouraging sweating.

FIG. 14 shows an embodiment of a system of the invention. A warm aircuff 310 is fitted around the legs 320 of a patient. The cuff 310 hasone or more hot air inlets 360 and one or more outlets 330. A relativehumidity sensor 350 is disposed at the hot air inlet 360. Dry warm airat a temperature of about 32° C. to about 45° C. at a relative lowhumidity of less than about 85% is fanned into the warm air cuff 310 atthe hot air inlet 360. The relative low humidity may, for example, beabout 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%,20%, 15%, 10%, or 5%. Air and sweat are exhausted from the cuff 310 atthe outlet 330. A second relative humidity sensor 340 is disposed at theoutlet 330.

In some embodiments, the chamber is sized to fit around a patient'sabdomen, one or two legs, one or two arms, a back, or any combinationthereof. In some instances, the chamber may cover a substantial portionof the patient's body below the chest, for example, covering around 1square meter of surface area and providing fluid loss at a rate ofapproximately 200 ml/hr.

The patient can request, or be prescribed, a certain amount of sweat pertreatment. The systems of the invention will calculate sweat rate,display, and stop the operation of the system once the desired sweatamount is obtained. Calculation can be performed using input from thetwo humidity sensors and their difference in readings over time, such asevery few minutes.

In another embodiment, the invention is directed to removing fluids fromthe body in order to maintain intravascular fluid balance by drivingfluids through the skin by osmosis, either alone or in combination withsweat production. A cuff with high concentration of intravascular largemolecules can be tight around the body legs arms or abdominal cavitiesand through a semipermeable cuff water or dry air will start to flow outthrough the skin and into the cuff. This way, fluids can shift out ofthe body and fluid balance can be maintained. This method can be done bythe patient at home and eliminate episodes of severe fluid overload.

FIG. 15 shows an embodiment of a system according to the invention. Heatcuffs are fitted around legs of a patient to reduce leg pitting edema. Acontrol panel is communicatively coupled to the heat cuff. The controlpanel includes a heat indicator and point of contact sweat contentindicator. The control panel is capable of communicating with atelemedicine portal to program and monitor the treatment.

In some embodiments, the invention is directed to a method of removingfluids through the skin by osmosis. The method comprises fitting achamber around a body part of a patient, the chamber comprisinginterstitial electrolytes. The method further comprises controllingcontent and concentration of the interstitial electrolytes in thechamber, thereby driving water and salts out of the body part of thepatient while maintaining pH and electrolyte levels of the body part.

FIG. 16 shows an embodiment of a system according to the invention. Apatient or subject 510 has a cuff 520 fitted around the patient'sabdomen. A control panel or controller 530 is communicatively coupled tothe cuff 510. The controller allows for communication with atelemedicine portal or network and the controller may comprise aplurality of sensors for monitoring of conditions of the cuff, such astemperature, sweat content, and humidity.

The cuff 520 may provide a wet environment with specific, controlledmineral content. For example, the mineral content is primarily salts andelectrolytes, such as sodium potassium and chloride. In such a scenario,creation of an osmotic pressure favoring outflow of fluids from thebody, not through sweat glands, is applied. The mineral content drivesfluids out of the body by the mechanism of osmosis and also balances theelectrolytes and mineral composition of the fluids as required in thebody.

In some embodiments of the invention, fluid loss may comprise salivageneration. The saliva glands can produce up to about 2.5 liters offluid per day. Stimulation of saliva glands can be achieved by chewinggum or any other material suitable as a stimulator. The saliva can becollected, measured, and analyzed. The system might have a flavor, suchas a flavored mouthpiece, that will stimulate production of saliva.

In certain embodiments, the invention is directed to a fluid lossstimulation device comprising a housing. The housing comprises amouthpiece, a storage chamber, and suction. The mouthpiece is disposedat a proximal end of the housing. The device comprises a power buttonfor providing power to the suction. For example, battery power may beused to power the suction, which may be any suitable suction component,such as a pump. The suction is configured to deposit saliva from a mouthof a patient into the storage chamber of the device. The storage chamberis removably detachable from the device. For example, the storagechamber may comprise a threaded end that is couples with threads on abody of the device. Rotation of the storage chamber results indetachment of the threaded components.

FIG. 17 shows a device for saliva production. The mouthpiece 610 of thedevice 600 is inserted into a mouth of a patient or subject. A suctioncomponent 620 is provided distal to the mouthpiece 610. The device 600includes a power button 630 that provides power to the suction component620, allowing for suction of saliva from the patient's mouth into thedevice. The saliva may be stored in a chamber 640, operably removablefrom the device 600 in order to empty the stored saliva. Optionally, thepatient may chew gum in order to stimulate fluid production duringtreatment.

The invention also recognizes that as sweat leaves the body throughskin, a portion of sodium from the sweat is re-absorbed back into thebody to maintain a proper salt balance. Without being limited by anyparticular theory or mechanism of action, it is believed that in certaininstances, the induction of sweating can lead to a salt imbalance sincewater is rapidly lost while sodium is re-absorbed back into the body. Incertain embodiments, if such imbalance does occur and needed to beaddressed, other methods and systems of the invention includeintroducing negative ions into an airflow that contacts a surface ofskin at a site where sweating is induced. Since sodium is positivelycharged, once sweat leaves the body in the presence of the negativeions, attractive forces between the positively charged sodium atoms andthe negatively charged ions prevent sodium being re-absorbed back intothe body, thereby preventing a salt imbalance.

Such methods and systems of the invention may include introducing anionsto a surface of a patient's skin at a site where sweating is induced.Anions may include any atomic or polyatomic ion with a negative charge.For example, the anions introduced by systems of the invention maycomprise any one of carbonate, sulphate, bromide, chloride, fluoride,iodide, nitride, oxide, or sulfide ions, or any combination thereof.

Methods and systems of the invention include adding negative ions to airthat flows through a chamber dimensioned for fitting around a body partto stimulate sweating. Negative ions can be put into the airflow by anynumber of methods capable of introducing ions into air in advance of theair contacting skin at the site of induced sweating. For example, insome embodiments, negative ions may be introduced into the airflow by anion-exchange resin or ion-exchange polymer. An ion resin is a resin orpolymer that functions as a medium for ion exchange and is generally inthe form of porous microbeads. The ion resin may be either strongly orweakly basic. In certain instances, methods and systems of the inventioninclude placing the ion resin at an inlet of the chamber such that asair flows through the inlet, the air passes through the ion resin toincorporate negative ions into the airflow. Ion resins can be purchasedcommercially or may be synthesized, for example, as described inJapanese Patent Application JP2002302665A, incorporated by reference.

In other embodiments, negative ions may be introduced into an airflowthat passes through a chamber by placing a negative ion generator at aninlet of the chamber. Negative ion generators considered by theinvention include any device capable of supplying negative ions to air,for example, such as those described in U.S. Pat. Nos. 3,403,252A,3,504,227A, 9,071,040, each of which are incorporated by reference. Forexample, salt can be dissolved in water. The water and the salts arethen sprayed into the air inflow line. Once in the air inflow line thehumid air now containing sodium and chloride anions passes through aresin that catches sodium ions. Flowing into a fluid stimulation systemworn around a patient's body are negatively charged ions at a relativelyhigh humidity (50%-75%). Providing anions at a relatively high humidity,capable to still evaporate sweat, will attract the sodium ions insidethe body to the skin and increase the sodium sweat concentration.

In certain aspects, methods and systems of the invention provide a fluidstimulation system with a chamber sized to fit around a body part of asubject to stimulate fluid loss. The chamber sized to leave a clearvolume of air between the body part and walls of the chamber. Thechamber includes an inlet and an outlet and is configured such that anair flow passes through the chamber from the inlet to the outlet. Theair flow may include negative ions introduced by a component of thesystem. For example, one of bromide, chloride, fluoride, iodide,nitride, oxide, or sulfide ions may be introduced into the airflow. Incertain instances, the component is an ion resin located near the inletof the chamber. Alternatively, the component may be a negative iongenerator located at an inlet of the chamber.

In other aspects, the invention provides methods for treating fluidoverload in a subject. Methods include shifting fluids directly andnon-invasively from an interstitial compartment of the subject to skinof the subject through controlled local fluid loss, thereby removingexcess fluid from the interstitial compartment of the subject andtreating fluid overload in the subject. Methods further includeintroducing negative ions into the airflow to inhibit sodiumre-absorption during fluid loss.

In some aspects, methods and systems of the invention provide a fluidremoval treatment device that patients can use on the go or from thecomfort of their home. Some embodiments provide a portable device thatcan be worn for a few hours or may be worn overnight to eliminate excessinterstitial fluid by sweating. The device may comprise an apparatussuch as a cuff, chamber, or sleeve that creates a controlled environmentaround a body part, such as, an arm, leg, abdomen, back, or acombination thereof. In some instances, the device can reduce afterloadby heating and increasing cutaneous vascular conductance. As such,patients may find using the device overnight is useful for treatingdyspnea and/or orthopnea to improve sleep.

In some embodiments, the invention provides a mobile apparatus such as acuff, chamber, or sleeve that a patient can wear around a body part tostimulate fluid loss while the patient is moving around. The apparatusmay be designed to allow freedom of movement so that the patient wearingthe apparatus can, for example, cycle or jog in it. In particular, theapparatus may be useful for improving exercise tolerance by reducingbreathlessness. In some instances, the apparatus is sized for wearingunderneath the person's clothes so that it is less apparent.

Methods and Devices to Remove Extracellular Fluid Overload (Edema) Viathe Skin

Extracellular Fluid Overload (Edema) is a medical condition in whichexcessive fluid accumulation in the intravascular and/or interstitialcompartments occur. If left untreated tissue function as well as gasexchange can be compromised leading to hospitalization.

The causes of the edema can be of many etiologies some of which areelevated intravascular hydrostatic pressures, changes in eitherintravascular or interstitial osmotic pressure, lymphedema, hypertensionand obesity.

Accordingly, the invention recognizes that methods and devices thatreduce edema whilst the patient is still in a chronic state and notacutely hospitalized could be very beneficial.

In some aspects, this disclosure provides systems and methods forstimulating fluid transfer through the skin in a subject for treatingchronic edematous clinical conditions in the subject and before theybecome acute heart failure episodes.

For example, fluid from the extracellular compartment can be removeddirectly from the skin by either sweat production in the sweat glands orvia the dermis by means of osmosis.

It is generally accepted that fluid removal rates ranging from 50ml/hr-300 ml/hr can enable prevention of excessive edema that if leftuntreated can lead to acute decompensation and hospitalization.

Fluid can flow out of the skin through the sweat glands at a rate ofliters per hour if the sweat glands are stimulated in the mostaggressive way. However, may not be tolerated by patients and may resultin a hemodynamic shock.

Therefore, a method and device that fits the patient fluid status isprovided herein.

The method may locally elevate a temperature of a patient's skin tovalues from 35° C. to 38.5° C. by applying warm (38° C.-44° C.) and lowhumidity (less than 40%) air environment around the patient's lower halfof the body for durations of 1 hr-6 hr. The timing may depend on factorssuch as edema severity. Such a method may achieve a fluid removal rateof between 100 ml/hr-300 ml/hr.

Air may be supplied by a generator console which has control of airtemperature, flow rate, humidity and additional parameters which assuresafe and effective operation. The lower part of the body is thepreferred area of treatment as it will be better tolerated by thepatient; however, the invention recognizes that other parts of the bodymay be treated, such as, the hands, chest, or back, especially if thoseother parts are edematous.

Partial body skin temperature elevation to values between 35° C. and38.5° C. are expected to maintain core body temperature at normal valueselevating no more than 0.5° C. at maximum and initiate sweat at a ratethat between 100 ml/hr-300 ml/hr when the part of the body that its skinpressure is elevated is the lower prat of the body from the abdomen andlower back down to the feet.

In some respects, part of the method may relate to treating a patienteither outside the hospital, i.e., in his home environment, or in theoutpatient clinics, so as to prevent acute medical conditions orhospitalization.

For the patient to tolerate daily or weekly 1-6 hr treatments, it isdesirable that the device enables the treated patient to be mobilewhilst being treated. Therefore, the console unit preferably enableselevation of the skin temperature to values between 35° C. and 38.5° C.while the patient can be mobile. As such, the patient may be mobilewhilst being treated. A specific apparatus may be worn by the patient,along with a specific heat generator, to enable mobility.

In some respects, this disclosure provides a uniquely designed wearable(dress) “capsule” and a mobile console. The wearable capsule may beloose around the lower part of the body or any part of the body in whichmovement of fluids from the extracellular compartment out of the bodyvia the skin are required. The capsule may be made from soft fabrics,for example, Neoprene, that are tightened around the lower ribs toprevent warn air from blowing towards the upper parts of the body or theface, or ridged material for example shell made of metal or polymers. Ata portion near the feet from a tightened belt the capsule may keep adistance of between 2 cm-10 cm from the skin when air flow is directedto the volume between the skin and the capsule wall.

When lying down, the capsule may be closed at the level of the feet toenable preservation of the warm air also at the flat position.

When standing or walking, the capsule may be opened at the level of thefeet to enable free movement of the body.

The capsule may include a console. The console may be a light weight,rechargeable, mobile stand which is connected to the wearable capsule bya tube at a distance of 0.5-2.0 meter. This tube delivers the air andthe electrical communication of the sensors are used to control theoperation of the system and the body parameters of the body.

When keeping the capsule loose from the body yet up to 10 cm away, thetrapped air volume can be between 0.2 cubic meter-0.5 cubic meter. Thisair volume can be heated from ambient temperature ranging from 17° C. to30° C. to, for example, a required temperature range of 38° C. to 45° C.

The required temperature range may cause the skin temperature to beelevated to the required range of 35° C. and 38.5° C. The requirement topreserve low humidity, for example, less than 50% also when the sweatrate is 300 ml/hr, may be crucial for the patient's treatment so thatsweat will not accumulate on the surface of the skin and will evaporate.If the sweat will not evaporate then the sweat rate will decrease andthe patient discomfort may lead to patient noncompliance.

At such a sweat rate and a base surrounding humidity of around 30% at40° C. the air flow through the capsule needs to be at least 0.2 cubicmeter per minute (cm/m) and preferably 0.3 cubic meter or more perminute (cm/m).

Taking at least some, and preferably all, these unique requirements willenable a mobile and effective treatment. Preferably, the design of thecapsule and its connection to a console based heater will include thefollowing specifications:

1. Power requirement: 80 watt-250 watt

2. 8 Amps-20 Amps

3. 12 VDC-48 VDC These top 3 requirements will enable temperatureincrease of around 20° C. at a heating rate of 1 minute

4. Air flow blower: up to 0.7 cmm

5. Capsule worn the chest (lower ribs) down to the feet, or as requiredto treat other parts of the body

6. At the upper level of the capsule a belt will be tightened to ensurethat air does not flow towards the upper levels of the body

7. The capsule has an option to be sealed at the level of the feet whenthe patient prefers to be treated when seating down or laying down

8. The warm air enters that capsule at the level of the knees

9. The heater is mounted on a pole that can be carried around the houseduring the treatments

10. The system can be operated and controlled via app. Installed on asmart phone of the user. The smart phone connected to the system by aslot in the console, allowing data recording, control and sharing of thedata.

FIG. 18 shows an example configuration of a device of the invention. Theheater unit may have any one or more of the following features:

-   -   1. Relative humidity of air inlet.    -   2. Relative humidity of air outflow from a humidity sensor at a        bottom of the capsule at the air outlet.    -   3. Temperature of capsule.    -   4. Temperature of skin on the calf as measured by a skin        temperature sensor.    -   5. Preset alarm and system shut down when skin temperature is        above 38.5° C. or capsule ambient temperature above 44° C.    -   6. Air flow rate.    -   7. Calculated sweat rate from the difference from inlet to        outlet absolute humidity multiplied by air flow rate.    -   8. Wireless sending of information to the physician status.

Accordingly, in some respects, this disclosure provides methods anddevices to reduce edema by enhancing fluid transfer through the skin.This disclosure may provide a mobile system, comprised of a wearable anda console, to elevate skin temperature to initiate sweat production. Forexample, a wearable device to create a warm air environment at apredetermined volume around the body to initiate sweat production andreduction of edema. Methods and devices may be controlled by smartphoneapplication.

Method and Apparatus to Treat Orthopnea and Paroxysmal Dyspnea (PND)

Orthopnea and PND are medical conditions in which patients feel thatthey cannot breathe freely in the supine or recumbent positions. Unlesstheir head is elevated, or their upper body is inclined, they cannotsleep at night or they wake up frequently feeling shortness of breath.

The supine or recumbent positions are important for maintaininghemostasis due to the diuretic effect in these positions. Therefore, andapart from the discomfort of not being able to sleep in supine, thesepatients do not produce urine output at a rate that they would have ifthey were laying supine.

Many Patients that suffer from Orthopnea and PND suffer also from Edemabecause of heart failure or Lymphedema. Treating or relieving theOrthopnea and PND can improve their ability to lay supine and maximizetheir diuresis during the night.

One of the main causes of Orthopnea is the pressure exerted by theabdomen on the diaphragm and the elevated pulmonary vasculaturepressures in the supine position.Both these causes either interfere with alveoli gas exchange orstimulate the receptors responsible for the shortness of breath feeling.

Therefore, an apparatus that will reduce the blood pressures or theabdomen pressure on the diaphragm can improve the shortness of breath,enable supine position with the enhanced diuresis and improve edemastatus.

Systems and methods of the invention recognize that there are at leasttwo separate apparatus features that may independently improve and mayreduce the pressures in the thoracic cavity:

1. Enabling vasodilation of the blood vessels to reduce blood pressuresand improve shortness of breath; and

2. Holding the abdomen from pushing on the diaphragm in the supineposition will enable the stretching of the diaphragm in the supineposition and reduction of pressure

An apparatus that can perform both features is novel and can improve themedical status of these patients.

Accordingly, in some respects, this disclosure provides an apparatusthat enables the following features:

A. Enabling Vasodilation of the Blood Vessels to Reduce Blood Pressuresand Improve Shortness of Breath.

The apparatus covers the lower part of the body from the chest down tothe feet. The apparatus can be made from fabrics that are loose aroundthe lower part of the body and tightened no the lower chest or abdomen.A warm air generator may produce temperatures between 37 and 45 degreesCelsius and at flow above 0.5 meter cube per minute. The war airgenerator may be connected to the apparatus and generate warm airenvironment surrounding the lower part of the body at controlledtemperatures. This warm air surrounding may create conditions which thevasculature, especially around the skin, is vasodilated.

The vasodilation may be controlled by the hypothalamus and the cutaneousvascular conductance receptors to thermoregulate the core bodytemperature. In addition to the initiation of sweating and itsevaporation, the body ensures that the core body temperature remainswithin a normal range.

The apparatus may ensure that the skin temperature is below 40 degreesCelsius by monitoring the skin temperature at the toe, or at any otherlocation in which the skin temperature is high, and whenever the readingis above 39 degrees Celsius, the warm air generator may stop to functionuntil the temperature drops down to 38 degrees Celsius.

Furthermore, the apparatus may use warn air generator at relativehumidity below 50% to ensure that if sweating occurs it will evaporateand will not cause discomfort to the patient.

B. Holding the Abdomen from Pushing on the Diaphragm in the SupinePosition

The upper part of the apparatus is tightened around the lower part ofthe chest and specifically around the lowest ribs and push the abdomentowards the pelvis and away from the diaphragm.

In the supine position this will enable full inspiration movement of thediaphragm with the accompanying low inspiration pressures. The apparatusmay employ any number of fastening mechanisms, such as, Velcro and/or azipper, to ensure that it does not slip down from its optimal position.

FIG. 19 shows an exemplary apparatus of the invention. The apparatusincludes a tight belt/Velcro at the lower chest level to push abdomendon towards the pelvis and to disable warm air flow towards the face.And, an arm air generator assembled to a loose fabric “capsule”elevating skin temperature, causing vasodilation, and reduction ofOrthopnea.

Accordingly, in some aspects, this disclosure provides, a method toreduce Orthopnea and PND shortness of breath and enable supine positionsleeping and/or enhanced diuresis when laying down. The method mayreduces blood pressure and enables diaphragm full inspirationstretching. An apparatus that increases the temperature at a part of thebody and as a result creates vasodilation of the vasculature, reducepressures and improved shortness of breath feeling. An apparatus thatpushes the abdomen away from the diaphragm by actively pressing orpulling the abdomen towards the pelvis.

Methods and Apparatus to Control Extracellular Electrolytes and FluidBalance Via the Skin

Extracellular electrolytes balance, especially sodium and potassiumconcentrations in the interstitial compartment are important to preservehemostasis and prevent water retention. Ways to control the electrolyteconcentration may include food and fluids intake or by drugs that workon the kidneys to either dispose of or preserve electrolyteconcentration.

In many pathologies, such as chronic kidney dysfunction (CKD) or heartfailure (HF) there is an electrolyte and fluid imbalance that leads tohospitalization or chronic need for dialysis.

Switching to another biological system, sweat glands secrete fluids fromthe interstitial compartment. The fluids that enter the secretory coilpart of the sweat gland is isotonic to plasma with Na+ concentrations ofaround 140 mmol/liter.

Once sweat flows towards the skin surface part of the sodium getsreabsorbed by the Apical and Basolateral membranes of the sweat ductaccording to the leak-pump model. Because of the reabsorption the Na+concentration on the skin is hypotonic and can range, depending on thesweat rate between 10 mmol/Liter-100 mmol/Liter. Controlling the sweatsodium concentration can have a great effect on the fluid status of apatient with CKD or HF and potentially prevent them from being fluidoverloaded.

The plasma Na+ concentration is strictly controlled between a smallrange of less than 10 mmol/Liter and therefore alterations from thisrange to either hypo or hypernatremia can have grave consequences.

In some aspects, this disclosure relates to methods and systems forcontrolling fluid and electrolytes such as sodium, potassium andchloride concentration by controlling their transfer through the skinduring sweat.

Applying a warm air environment around a part of the body may initiatesweat when the skin temperature elevates above 33 degrees Celsius. Toensure that the skin does not start to burn, the temperature of the skinis preferably always be kept below 39 degrees Celsius.

Methods disclosed herein may control the reabsorption rate of the sodiumions at the duct by attracting them to the skin surface using anegatively charged ion at specific relative humidity environmentproduced by the apparatus on the skin surface or in the air surroundingthe skin.

For example, if surrounding the skin, whilst sweating is stimulated,would be a negatively charged carbonate CO3 or OH anion, the sodiumcations in the duct may enhance the flow towards the skin rather thanbeing diffusing into the apical membrane. The reabsorption rate of thesodium into the interstitial compartment of the skin will be reduced andthe sodium concertation will not elevate. This clinically could be verymeaningful as the electrolytes, especially the sodium, determines edemastatus by binding to fluids.

In some aspects, this disclosure provides a combination of stimulatingsweat production and controlling the electrolytes reabsorption rate,thus increasing or decreasing the extravascular sodium and potassium orany other electrolyte concentration.

One example of an apparatus of the invention includes a single, ormultiple use, 2 stage apparatus that is placed in the air inflow line ofa warm air generator to increase the skin temperature to initiatesweating.

In the first stage of the apparatus, a soluble salt such as K2CO3 may bedispersed into the inflow of air at a temperature of, for example, 40degrees Celsius-46 degrees Celsius and at a relative humidity of between30%-50%.

The salt may be soluble and may naturally separate into cations andanions.

In the second part of the apparatus, the air with the K2+CO3− ions maybe passed through a cation resin filter beads that filter the cationsand only allow for the anion in the air (H+ and K2+) to flow onto theskin inside the apparatus.

The air, being negatively charged, may increase sodium attraction to theskin surface from the ion bonding attraction and as a result, decreasethe reabsorption rate of the sodium. Preferably, the sodiumconcentration in the interstitial compartment will decrease in additionwith plasma sodium levels.

Another apparatus may be a filter. The filter may be placed online tothe air inflow line in which all the current electrolytes in the air arefiltered. An environment of humidity of around 50% may be created bypassing the air into a hydrated environment. As a result, the capacityof the air to attract the sodium cations may increase as they will bindto the negative ions of the humid air water molecules.

Other methods for attracting the sodium molecules to the skin surfacemay involve using a negative hydrostatic pressure environment whilststimulating sweat. The negative hydrostatic pressure may enhance sweatflow to the skin and increase the sodium concentration on the skin andreduce its interstitial concentration.

An exemplary apparatus may be a permeable container loaded into theinflow of the air and having K2CO3 salt that has a solubility in moistair that is very high. Once partially dissolved, CO3 anions will thenattract the Na+ electrolytes from the sweat duct and will reduce theirreabsorption.

Accordingly, in some aspects, this disclosure relates to a method toreduce sodium concentrations in the plasma and interstitial compartmentby enhancing sweat rate and pulling to the skin surface the sodiumcations using air having negatively charged anions.

Furthermore, this disclosure may provide an apparatus for enhancingsweat using warm air generated into a wearable around the body elevatingthe skin temperature to levels of between 33-39 degrees Celsius.Furthermore, in the warm humid air inline pipe there is a 2 stagedisposable apparatus: The first stage is a disperser a soluble salt intothe humid air. As the air flows through the disperser the air becomesfull with ions. The next stage is to pass the ion filled air through acation resin filter. The warm air that will exit the filter and flowaround the skin will be negatively charged at huminites around 50%. Thisair when flowing around the sweating skin will pull the sodium ions tothe skin surface and reduce its reabsorption

Methods and Apparatus to Control Extracellular Electrolytes and FluidBalance Via the Skin

Patients with heart failure suffer from frequent fluid overload in theinterstitial and intravascular compartments as a result of elevatedhydrostatic or osmotic or both these pressures within the capillaries.The elevated pressures lead to fluid overload formation. This is aserious medical condition and can become a life-threatening.

Current therapies mostly rely on drugs that reduce intravascular volumeand pressure by enhancing urine production. These therapies requirecomplicated sequence of clinical events and often lead to kidneydysfunction, drug resistance and inefficient treatments. New therapiesare highly required to meet this great unmet clinical need that millionsof patients suffer from.

The fluids in the interstitial compartment supply the sweat fluids tothe eccrine glands and therefore can be secreted out of the body througha natural pathway of these glands through the skin. This natural pathwaycan be used to decongest fluid overload and treat HF patients. In orderto efficiently decongest these patients suffering from fluid overloadthrough the skin a sweat rate of between 100 ml/hr-500 ml/hr isrecommended. Lower rates may not be efficient and too high rates can bedangerous and lead to hypotension.

It is highly recommended to have an option to treat the patients also athome and therefore a controlled and automated system that will decongestthe patient's fluid overload without the requirement of in-hospital staynor constant monitoring can be beneficial. There are currently nomethods nor devices to treat patient fluid overload by enhancing fluiddecongestion through the skin.

There are several methods by which to promote fluid transfer through theskin. For example: Elevation of core temperature, however, it may bedifficult for HF patients that will not tolerate the increase in core Theat; neural stimulation by drugs, although may not be tolerable forlong durations; elevation of skin temperature, which is a preferredmethod by which to promote perspiration and be tolerable and evencomfortable for the patients if subjected only to the lower part of thebody from the chest down.

The skin starts to sweat at skin temperatures of usually over 33 degreesCelsius, but varies from one person to the other.

Accordingly, in some aspects, this disclosure provides both a method andapparatus for decongesting fluid overloaded patients by elevating andcontrolling partial body skin temperature to values over 36 degreesCelsius and typically between 37-39 degrees Celsius. These skintemperatures may enhance fluid flow from the edematous regions in theinterstitial compartment to the eccrine sweat glands and out to theskin. Immediate evaporation of the sweat on the skin may be accomplishedby the low humidity and continuous airflow that elevated the skintemperature. The evaporation process cools down also the blood flowingto the skin and upon its return to the deeper vasculature it ensuresthat the core body temperature remains within normal values. Thiseffective treatment can be performed whilst maintaining core temperaturevalues, HR and BP at baseline/normal levels.

In some aspects, this disclosure describes an apparatus that elevatespartial body skin temperature by covering part of the patient with aloose and self-wearable fabric that is worn around the chest and upperback all the way down to the feet, preferably, including the toes. Atighter elastic band of up to about 5 cm wide or a tightening string,may be placed around the chest and lower back of the wearable fabric,and may be built in so as to eliminate any air flow in nor out towardsthe face and head from that region.

The fabric may be made form a mesh, for example, as shown in FIG. 22 .The mesh ensures flow of air to every region of the body thus enablingsweating and evaporation. Due to the mesh structure even when thepatient is seated down, the patient may touch the wearable just at avery small region whilst around it the air still flows, elevates theskin temperature and evaporates the sweat when it flows out.

Preferably, there is an air inlet port and an air outlet port atopposite sides of the wearable. The inlet may be at the feet and theoutlet may be at a level of the chest, or visa versa. Warm air from aheater may be directed into the wearable from the inlet port. The aircan be diverted using smaller tubes to all parts of the body as can beseen from the FIG. 20 . The warm air may heat up the skin temperatureuntil it initiates sweating. The air may leave the wearable at higherhumidity then its inlet humidity as it now has the sweat that evaporatedfrom the skin in it. The air may evaporate the sweat very quickly as therelative humidity will always be kept below, for example, 40% at theinlet ensuring that also with maximal sweat rates at the outflow thehumidity will not exceed, for example, 60%.

The warm air may initiate sweat when the skin temperature elevates abovea certain temperature that varies slightly between one person to theother but in general may be above 32 degrees Celsius and below 36degrees. Above this onset temperature the sweat rate may increases asthe temperature elevates. To ensure that the skin does not start toburn, the temperature of the skin may be kept below 42 degrees Celsius.

In some aspects, the invention also provides an apparatus that comprisesof a control unit and input sensors and meters, which may include anyone or more of:

1. A skin temperature sensor placed on a part of the body that itstemperature is being raised. It can be on the leg, abdomen, torso orback;2. Two relative humidity and temperature sensors, placed one at the warmair inflow line and the second at the warm air outflow port. Onlinereadings may be sent to the control unit that then calculates theabsolute humidity form the relative humidity and temperature;3. Air flow meter placed in the inflow line measuring continuously theair flow rate into the wearable. The online readings may be sent to thecontrol unit;4. A weight scale to measure the patient's weight before the procedureand at the end of the procedure. The weight sends the recording to thecontrol unit;5. A warm air heater that is set to deliver air at temperatures betweenabout 37 degrees Celsius and 55 degrees Celsius and at relative humidityof up to 40% at 40 degrees Celsius; and6. A control unit that receives input readings from the above sensorsand meters calculates the sweat rates by subtracting the inlet from theoutlet absolute humidity and then multiply by the air flow rate. Thecalculated sweat rate is then evaluated relative to the required sweatrate and the required weight loss.

In instances where the sweat rate is too low or too high or the relativehumidity elevates above, for example 60%, the control unit may set theinflow air temperature and flow rate to meet the desired sweat rate andweight loss that's required per treatment and reduce the relativehumidity to enable immediate evaporation. The control unit may also sendthe information and treatment parameters by the internet to the treatingnurse or physician.

An algorithm executed by the control unit is presented in FIG. 25 . Thealgorithm ensures that a treatment is set automatically with maximalsafety and is thus suitable to, for example, an elderly patient thatcannot operate devices that require complicated operation and thinking.

For example:

-   -   The patient is told that his target weight should be 80 kg.    -   The patient turns on the device and the target weight is being        set in the set up screen or sent by the physician by the home        wireless internet.    -   He weighs himself on the integrated system weight and he is 81        kg.    -   The system generates a signal or a voice telling the patient        that he will be treated for 3-5 hours depending on the sweat        rate.    -   The patient wears the wearable and the system automatically        starts to send in warm air at 40° C. and relative humidity per        the ambient air but less than 40% and at a flow rate of 0.5        cubic meter/minute (CMM)    -   The system measures the relative humidity and temperature at the        outlet and inlet ports and calculates the sweat rate. For        example, the calculated sweat rate is 150 ml/hr and the relative        humidity is 75%. The system will increase the flow rate to        reduce the humidity to less than 60% (to enable full        evaporation, more efficient sweating and maintaining core        temperature at normal levels).    -   If the skin temperature is below 37° C. the system will also        elevate the input temperature until the skin T is above 38° C.        but less than 40° C.    -   Once the system detects a sweat rate of 2001 ml/hr and skin T        between 37-39 degrees and relative humidity below 60% then the        system will set these parameters and determine the treatment        duration.    -   Once the calculated targeted weight is met the system stops the        operation and the patient is asked to weigh again.

FIG. 20 shows a side view of a wearable apparatus according to aspectsof the invention.

FIG. 21 shows a front view of a wearable apparatus according to aspectsof the invention. As depicted, air is dispersed and diverted to allparts of the body.

FIGS. 22 & 23 show a cross sectional view of a wearable apparatus. Thecross section shows the mesh to lower contact area of patient. Thetubing spreads the air to all body parts making the skin temperaturehomogenous.

FIG. 24 shows another view of a wearable apparatus according to aspectsof the invention.

FIG. 25 shows a diagraph of a system algorithm. In particular, FIG. 25shows a built-in algorithm for enabling a safe and effective procedure.

The invention has been tested and proven to work as specified in humantrials on healthy and fluid overloaded patients. The sweat rate of 9consecutive treatments on 3 fluid overloaded patients resulted in anaverage fluid loss of 250 ml(gr)/hr. In 4 hours of treatment the weightloss was more than 1 Kg.

FIG. 26 shows results from 4 hours experiment on HF, fluid overloadedpatients.

FIG. 27 shows an example of the calculation performed from the onlinehumidity sensors and the air flow meter.

FIG. 28 shows results from the 3rd patient treated during his 3rdtreatment. As it can be seen from the clinical results, the inventionworks and efficiently decongests, non-invasively, the fluid overload inpatients.

FIG. 29 shows a built-in algorithm executable by a counsel of theinvention. The algorithm is designed to enable safe, automated and verysimple use of procedure.

FIG. 30 shows clinical data from six treated subjects. The data relatesto renal function tests.

FIG. 31 shows treatment results. Shown are patient images taken before,during, and after a fluid removal treatment. As shown, treating apatient for Edema (swelling) by transferring fluids through thepatient's skin, successfully alleviates swelling.

FIG. 32 shows clinical data. The data are taken from normal sixsubjects, e.g., not subjects suffering from heart failure. The data showchanges in sweat rate during procedure and total weight loss as a resultof treatment. Of note, the weight loss during treatment from sweating isapproximately 200 gr/hr. During treatment, blood pressure, heart rate,core temperature, urine output, and blood electrolytes remained atbaseline levels.

FIG. 33 shows clinical data. The data are taken from seven heart failuresubjects. Of note, the weight loss from sweating was approximately 235gr/hr. In 4 hours, net weight loss was approximately 1 Kg. Duringtreatment, blood pressure, heart rate, core temperature, urine output,and blood electrolytes remained at baseline levels.

FIG. 34 shows data relating to sweat rate. The sweat rate (ml/hr) iscalculated from humidity sensors, during patient treatments.

Accordingly, in some aspects, this disclosure provides a method forremoving fluid overload from the interstitial and intravascularcompartments by promoting their flow to the eccrine sweat glands and outto the skin by elevating partial body skin temperature only.Alternatively, or in addition to, this disclosure provides a method forcontrolling skin temperature and sweat rate by closing a control loopinputting relative humidity at the inflow and the outflow, the air flowrate and the skin temperature and changing the flow rate and inflow airtemperature until a sufficient sweat rate is achieved. The apparatus mayhave a weight built in that inputs the baseline and final weights to thesystem that can then send the information, for example, by the internet,to the treating physician. The apparatus may be worn around a body part,for example, from the chest and upper back down to the feet and toes.The apparatus may enable free flow of air inside the apparatus andevaporate all the sweat as it increases the air flow rate to ensure thatthe relative humidity is less than 60%. The apparatus may have a crosssection with a mesh fabric that contacts the skin at very small areathus enabling free flow and sweat evaporation in maximal areas. Theapparatus may have an airflow dispersion system incorporated inside themesh that spreads the air evenly in the wearable thus ensuringhomogenous temperatures around the body and by such optimizing totalsweat rate.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A fluid stimulation system comprising: a chamber sized to fit arounda body part of a subject to stimulate fluid loss in the subject, leavingclear volume of air between the body part and walls of the chamber, thechamber comprising an inlet and an outlet and the chamber beingconfigured such that an air flow passes through the chamber from theinlet to the outlet; and first and second relative humidity andtemperature sensors, wherein the first relative humidity sensor isoperably located at the inlet and the second relative humidity sensor isoperably located proximate the outlet.
 2. The system of claim 1, whereinthe air flow includes negative ions that are introduced by a componentof the fluid stimulation system.
 3. The system of claim 2, wherein thenegative ions comprise one of bromide, chloride, fluoride, iodide,nitride, oxide, or sulfide ions.
 4. The system of claim 3, wherein thecomponent is one of a negative ion generator or an ion resin located atthe inlet of the chamber.
 5. The system of claim 4, wherein the fluid issweat.
 6. The system of claim 5, further comprising: a controllercommunicatively coupled with a plurality of sensors that provide data tothe controller for calculating sweat rate within the chamber, thecontroller comprising a processor configured to control and monitorconditions of the chamber and operable by a user to program conditionsof the chamber.
 7. The system of claim 6, further comprising a gasmixture with or without air.
 8. The system of claim 6, furthercomprising an air fan and heat source coupled to the chamber.
 9. Thesystem of claim 8, further comprising an inflow flow meter associatedwith the air fan.
 10. The system of claim 9, wherein the flow meter iscommunicatively coupled with the controller and data from the flow meteris used for calculation of the sweat rate within the chamber.
 11. Thesystem of claim 6, wherein the controller is used to analyze sweatcontent and recommend nutritional supplement.
 12. The system of claim 5,further comprising an exercise device disposed in the chamber, theexercise device for use by the patient to encourage sweating.
 13. Thesystem of claim 12, wherein the exercise device comprises a pedalexercise device or an anaerobic spring exercise device.
 14. The systemof claim 2, wherein the body part comprises one or more legs, one ormore arms, a torso, a lower back, or an abdomen.
 15. The system of claim14, wherein the abdomen comprises up to a chest level and below a heartlevel.
 16. The system of claim 2, wherein an interior of the chamber isconfigured such that walls of the chamber are kept spaced from the bodypart of the subject.
 17. The system of claim 2, wherein walls of thechamber have direct contact with the body part.
 18. The system of claim2, further comprising a skin temperature sensor.
 19. A method fortreating fluid overload in a subject, the method comprising shiftingfluids directly and non-invasively from an interstitial compartment ofthe subject to skin of the subject through controlled local fluid loss,thereby removing excess fluid from the interstitial compartment of thesubject and treating fluid overload in the subject, wherein the fluidloss is sweating, and wherein sweating is stimulated by controllingrelative humidity, airflow, pressure, and temperature within a chamber.20. (canceled)
 21. (canceled)
 22. The method of claim 19, furtherincluding introducing negative ions into the airflow to inhibit sodiumre-absorption during sweating.
 23. The method of claim 22, wherein thenegative ions comprise one of bromide, chloride, fluoride, iodide,nitride, oxide, or sulfide ions.
 24. The method of claim 23, furthercomprising calculating a sweat rate within the chamber.
 25. The methodof claim 23, further comprising aerobic or anaerobic exercising of abody part of the subject within the chamber to encourage sweating. 26.The method of claim 23, further comprising analyzing sweat content andrecommending nutritional supplement.
 27. The method of claim 23, whereinthe method is carried out using a sweat stimulation system.
 28. Themethod of claim 27, wherein the sweat stimulation system comprises: achamber sized to fit around a body part of a subject, leaving clearvolume of air between the body part and walls of the chamber, thechamber comprising an inlet and an outlet and the chamber beingconfigured such that an air flow passes through the chamber from theinlet to the outlet; and first and second relative humidity andtemperature sensors, wherein the first relative humidity sensor isoperably located proximate the inlet and the second relative humiditysensor is operably located proximate the outlet.
 29. The method of claim28, wherein the negative ions are introduced by one of a negative iongenerator or an ion resin that is located at the inlet of the chamber.30. The method of claim 29, wherein a plurality of sensors provides datato a controller for calculating sweat rate within the chamber.
 31. Themethod of claim 30, further comprising controlling and monitoringconditions of the chamber using the controller, wherein the controlleris operable by a user to program conditions of the chamber.
 32. Themethod of claim 19, further comprising monitoring skin temperature ofthe subject and stopping operation of the system if the skin temperatureexceeds 38° C.
 33. A method of removing fluids through the skin byosmosis comprising: fitting a chamber around a body part of a patient,the chamber comprising interstitial electrolytes; and controllingcontent and concentration of the interstitial electrolytes in thechamber, thereby driving water and salts out of the body part of thepatient while maintaining pH and electrolyte levels of the body part.34.-38. (canceled)
 39. A method to reduce edema by enhancing fluidtransfer through the skin, wherein the enhancing fluid transfer iscontrolled by a smartphone application. 40.-42. (canceled)
 43. A systemto reduce edema by enhancing fluid transfer through the skin, whereinthe system is controlled by a smartphone application. 44.-56. (canceled)57. A method for treating fluid overload in a subject, the methodcomprising shifting fluids directly and non-invasively from aninterstitial compartment of the subject to skin of the subject throughcontrolled local fluid loss, thereby removing excess fluid from theinterstitial compartment of the subject and treating fluid overload inthe subject, wherein the fluid loss is sweating that is stimulated byelevating skin temperature of the subject within a chamber.